This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Presenilin is the catalytic subunit of gamma-secretase involved in the intramemebranous processing of amyloid precursor protein, producing beta-amyloid protein of Alzheimer?s disease. In order to understand the catalytic mechanism of presenilin, a group of prokaryotic proteins containing highly similar active site sequence motif, was selected for structural studies. These proteins are responsible for removing the N terminal signal peptide and then facilitating the further processing for target proteins. The high-resolution structure of this group of intramembrane proteases will aid a better understanding of the mechanism of presenilin, a key player in Alzheimer?s disease.